Persistent anemia is a known consequence of Parvovirus B19 (B19) infection following renal transplantation. However, to date, no description of B19-related hemophagocytic lymphohistiocytosis (HLH) exists in renal transplant recipients. We report a 24-year-old male kidney recipient, who presented with fever, severe anemia and allograft dysfunction two years following transplantation. Hyperferritinemia, hypertriglyceridemia, elevated serum lactate dehydrogenase, pancytopenia and fragmented red blood cells on the peripheral blood were also noted. Bone marrow examination revealed giant pronormoblasts and frequent histiocytes with intracellular hematopoietic elements, consistent with HLH. Renal allograft biopsy revealed closure of the lumen of glomerular capillaries and thickening of the capillary walls compatible with thrombotic microangiopathy. The presence of anti-B19 IgM antibody and viral DNA in the patient's serum (detected by real-time PCR) confirmed an acute B19 infection. Following high-dose intravenous immunoglobulin therapy, the anemia gradually resolved and renal function improved. As far as we know, this is the first report of B19-associated HLH and thrombotic microangiopathy in a renal transplant recipient. Â© 2008 The Authors

Ardalan, M.R.

Esmaili, H.

Keyvani, H.

Shoja, M.M.

Tubbs, R.S.

eprints Iran University of Medical Sciences

American Journal of Transplantation 2008; 8: 1340–1344Blackwell MunksgaardC© 2008 The AuthorsJournal compilation C© 2008 The American Society ofTransplantation and the American Society of Transplant Surgeonsdoi: 10.1111/j.1600-6143.2008.02244.xCase ReportPostrenal Transplant HemophagocyticLymphohistiocytosis and ThromboticMicroangiopathy Associated withParvovirus B19 InfectionM. R. Ardalana,b, M. M. Shojab,∗,R. S. Tubbsc, H. Esmailid and H. KeyvanieaDepartment of Nephrology,bTuberculosis and Lung Disease Research Center, TabrizUniversity of Medical Sciences, Tabriz, IrancDepartment of Cell Biology, University of Alabama atBirmingham, ALdDepartment of Pathology, Tabriz University of MedicalSciences, Tabriz, IraneDepartment of Medical Virology, Iran University ofMedical Sciences, Tehran, Iran∗Corresponding author: Mohammadali M. Shoja,shoja.m@gmail.comPersistent anemia is a known consequence of Par-vovirus B19 (B19) infection following renal transplan-tation. However, to date, no description of B19-relatedhemophagocytic lymphohistiocytosis (HLH) exists inrenal transplant recipients. We report a 24-year-oldmale kidney recipient, who presented with fever,severe anemia and allograft dysfunction two yearsfollowing transplantation. Hyperferritinemia, hyper-triglyceridemia, elevated serum lactate dehydroge-nase, pancytopenia and fragmented red blood cells onthe peripheral blood were also noted. Bone marrowexamination revealed giant pronormoblasts and fre-quent histiocytes with intracellular hematopoietic el-ements, consistent with HLH. Renal allograft biopsyrevealed closure of the lumen of glomerular capillariesand thickening of the capillary walls compatible withthrombotic microangiopathy. The presence of anti-B19IgM antibody and viral DNA in the patient’s serum (de-tected by real-time PCR) confirmed an acute B19 infec-tion. Following high-dose intravenous immunoglobu-lin therapy, the anemia gradually resolved and renalfunction improved. As far as we know, this is the firstreport of B19-associated HLH and thrombotic microan-giopathy in a renal transplant recipient.Key words: Hemophagocytic lymphohistiocytosis, in-travenous immunoglobulin, Parvovirus B19, renaltransplantation, thrombotic microangiopathyReceived 04 January 2008, revised 25 February 2008and accepted for publication 12 March 2008IntroductionHemophagocytic lymphohistiocytosis (HLH) is a hetero-geneous clinicopathological entity associated with uncon-trolled and ineffective immune activation leading to cellulardamage and multiorgan dysfunction as well as excessiveactivation of the benign macrophages in the bone marrow,spleen and lymph nodes (1,2). The activated macrophagesthen transform into histiocytes phagocytizing erythro-cytes, leukocytes, platelets and their precursor cells lead-ing to various degrees of cytopenia, hepatosplenomegalyand lymphadenopathy. Excessive production of differentcytokines including tumor necrosis factor (TNF)-alpha,interleukin-6, interleukin-8 and interferon-gamma are im-plicated in the pathogenesis of HLH (2). HLH can developin patients with hereditary immune dysfunction, infections,neoplastic or autoimmune diseases (1). A familial form ofHLH does also exist. The presence of hemophagocytosis inthe bone marrow, spleen or lymph nodes, elevated serumlactic dehydrogenase (LDH >1000 IU/L), hyperferritinemia(>500 ng/mL), hypertriglyceridemia (>3 mmol/L), hypofib-rinogenemia (<1.5 g/L), low or absent natural killer cell cy-totoxicity, elevated soluble IL-2 receptor (>2400 U/mL),cytopenia affecting at least two cell lineages (platelets<100 000/lL or neutrophils <1000/lL) are suggestive ofthis entity (1–4).Parvovirus B19 (B19) is the only member of the familyParvoviridae. Infection with B19 is a known cause of ery-thema infectiosum, polyarthropathy syndromes, erythroidhypoplasia and aplastic anemia in healthy individuals (5).In renal transplant recipients, B19 infection may enter thebody via the respiratory tree or transplanted organ, or maybe reactivated from a latent infection (6). This infection isassociated with refractory and recurrent anemia, glumeru-lopathy, proteinuria, microscopic vasculitis, thrombotic mi-croangiopathy (TMA), hepatitis and severe encephalitis inrenal transplant recipients (7–13). Herein, we report a re-nal transplant recipient with severe anemia, allograft dys-function, TMA and HLH two years following transplanta-tion. Acute B19 infection was ascertained by positive anti-B19 IgM titer and the presence of high-serum viral load.To the best of our knowledge, this is the first report ofB19-associated HLH in a renal transplant recipient.1340Parvovirus B19 and Renal TransplantationCase ReportIn April 2007, a 24-year-old male was admitted for a three-week onset of fever and severe anemia. The patient hadreceived a living, unrelated renal transplantation two yearspreviously and was on triple immunosuppressive ther-apy including cyclosporine (200 mg/day), mycophenolatemofetile (2 gm/day) and prednisolone (5 mg/day). The base-line blood cyclosporine level was 280 ng/mL, and theserum creatinine level was 1.2 mg/dL. His past medicalhistory revealed the onset of postrenal transplant diabetesmellitus three months earlier after which the patient hadreceived insulin. At that time, his hemoglobin level was17.5 g/dL. The family history was unrevealing.On physical examination, blood pressure was 100/60mmHg and body temperature was 38◦C. The patient wasalert and oriented. No rash or icter was noted. Hep-atosplenomegaly or lymphadenopathy was not found. Thephysical examination was otherwise unremarkable. On ad-mission laboratory findings are summarized in Table 1.There was a normochromic-normocytic anemia. The pa-tient received packed red blood cell infusion. Serum ferritin,LDH and fasting triglyceride levels were elevated. Serumcreatinine level was 3 mg/dL. A urine dipstick test re-vealed moderate proteinuria. A 24-hour urine volume wasTable 1: On admission laboratory findings in the present patientNormal rangeLevel (for male)Hemoglobin (g/dL) 5.5 13–18White blood cell count(lL−)5200 3600–11 200Platelet count (lL−) 120 000 140 000–440 000Mean corpuscularvolume (fL)94 74–96Mean corpuscularhemoglobin (pg)30 28–32Mean corpuscularhemoglobinconcentration (g/dL)31.8 30–36Serum ferritin (ng/mL) > 800 12–300Fasting triglyceride(mg/dL)372 (or 4.2 mmol/L) <265 (or <3 mmol/L)Lactatedehydrogenase(U/L)3124 90–250Alanineaminotransferase(U/L)113 10–55Aspartateaminotransferase(U/L)132 10–40Total cholesterol(mg/dL)185 <200Fasting blood sugar(mg/dL)82 <100Serum cyclosporine(ng/L)195 -2200 mL with a urine protein-to-creatinine ratio of 0.51.Prothrombin and partial thromboplastin times were withinnormal limits. Peripheral blood examination revealed fre-quent helmet cells. Renal allograft Doppler ultrasonogra-phy disclosed a normal size renal allograft with normal cor-ticomedullary differentiation and echogenicity. Intra-renalarterial resistive index was within normal limit. Upper gas-trointestinal endoscopy was unrevealing. The platelet andwhite blood cell count nadirs were 39 000/lL and 2400/lL(53% polymorphonuclear cells) at days 5–7 of admission.Serological studies for Epstein-Bar virus (EBV), hepatitis B,C and E and human immunodeficiency virus (HIV) werenegative. Hepatitis B surface antigen was negative. Anti-hepatitis A IgM antibody was negative and IgG antibodywas positive, consistent with previous infection. A neg-ative anticytomegalovirus IgM and positive IgG titer werealso detected (anti-CMV IgG also was positive before trans-plantation). Serological tests for parovirus B-19 infectionwere performed (using enzyme-linked immunosorbent as-say; DRG instruments, GmbH, Germany), which was posi-tive for anti-B19 IgM antibody. Subsequently, B19 viral DNAwas detected in the serum by nested polymerase chain re-action (PCR) using the major capsid protein (VP2)-encodingsequence of B19 as described by Cassinotti et al. (14). Thereal-time PCR (with Artus RealArtTM Parvo B19 LC PCR kit)revealed a viral load higher than 104 IU/L.Bone marrow aspiration and biopsy disclosed erythroidimmaturity with a left shift and occasional giant pronor-moblasts with dark-blue cytoplasm (Figure 1). Myeloid andmegakaryocytic linages were normal in appearance. Nu-merous large histiocytes with engulfed lymphocyte, poly-morphonuclear and red blood cells were prominent, whichFigure 1: Bone marrow containing giant pronormoblasts(star) with dark-blue cytoplasm (Giemsa, 1000×).American Journal of Transplantation 2008; 8: 1340–1344 1341Ardalan et al.Figure 2: Bone marrow histiocyte (star) with intracellularhematopoietic elements (Giemsa, 1000×).were suggestive of hemophagocytosis (Figure 2). A per-cutaneous renal allograft needle biopsy was performedat day 3 of admission. Light microscopic examination ofrenal biopsy specimens (Figure 3) revealed the luminalnarrowing of glomerular capillaries, thickening of glomeru-lar capillary walls and duplication of the glomerular base-ment membrane, endothelial swelling and some areasof capillary loop closure, all of which were compatiblewith subacute glomerular involvement due to thromboticmicroangiopathy.Figure 3: Glumerulus showing closed capillary lumens, thick-ening of capillary walls and duplication of the glomerularbasement membrane.Subsequently, high-dose intravenous immunoglobulin(IVIG, 400 mg/kg/day for five days) was administered atday 8 of admission. The prescribed dose of mycopheno-late mofetil was reduced to 1 gm/day. The patient’s gen-eral condition gradually improved and his fever subsided.On day 20 of admission, the patient’s serum creatininedeclined to 2 mg/dL and hemoglobin level increased to9.5 mg/dL. On a follow-up visit, three months followingdischarge, hemoglobin was 14 g/dL, WBC count 9000/lLand platelet count 234 000/lL. Serum creatinine level was1.2 mg/dL. Serological studies revealed a positive anti-B19IgG and negative IgM titers. A 2 g/day dose of MMF dosagewas restarted and the patient was scheduled to have reg-ular follow-up visits.DiscussionIn the present case, the diagnosis of HLH was made by thesuggestive bone marrow and laboratory findings (2,15,16).Elevated serum ferritin, hypertriglyceridemia, severe ane-mia and decreased platelet count were also compatiblewith HLH (1,3). The diagnosis of B19 infection was primar-ily obtained by the presence of anti-B19 IgM antibodiesand viral DNA in the patient’s serum. Additionally, the pres-ence of fragmented red blood cells in the peripheral blood,hemolysis and renal histopathology were consistent withTMA. The temporal association of HLH, TMA and positiveB19 serology and PCR led us to attribute the present sce-nario to an acute B19 infection.The natural history and outcome of infection-associatedHLH may depend on the inciting pathogen. EBV is the mostcommon triggering agent (2). In a series of 219 childrenwith infection-associated HLH, EBV infection was associ-ated with a higher mortality (17). Usually treatment of thetriggering infections is ineffective and severe cases mayrequire chemotherapy and bone marrow transplant (2). Cy-tomegalovirus has been described as a cause of HLH intransplant recipients and is associated with a poor outcome(2,18). However, recovery has been reported following spe-cific anticytomegalovirus therapy (19). HLH due to B19infection carries a better prognosis compared with othervirus-associated HLH and most patients with this compli-cation may survive without specific therapy (2). The mostcommon underlying disease in B19 related HLH is heredi-tary spherocytosis (2).Since the first report of B19 associated HLH (20), fewsimilar cases have been described (21–24). To date about30 such cases have been reported in children and adults.None of these has occurred following kidney transplanta-tion. In a series of 17 renal transplant recipients with HLH,nine patients had viral infection with cytomegalovirus,Epstein-Barr virus and human herpesvirus 6 and 8, whileno case of B19 infection was reported (25). Infectionswith BK virus, Mycobacterium tuberculosis, Toxoplasma,Escherichia coli, Bartonella henselae and Pneumocystis1342 American Journal of Transplantation 2008; 8: 1340–1344Parvovirus B19 and Renal Transplantationcarinii have also been reported as the cause of HLH fol-lowing renal transplantation (25–28). Hence, performing anextensive workup for the infectious causes of HLH is nec-essary as some infections can trigger HLH and the man-agement is different depending on the case.In the present patient, renal allograft histopathology wascompatible with TMA. This type of B19-related glomeru-lopathy has been reported by Murer et al. (7). Collapsingglomerulopathy, minimal change disease and TMA withnephrotic syndrome have been described in a small seriesof HLH patients (29). It has been proposed that in HLH, highlevels of inflammatory cytokines particularly TNF-alpha caninjure podocytes leading to glomerular collapse and tubu-lar necrosis with subsequent proteinuria and renal dys-function (29–31). In the present patient, anemia, protein-uria and renal allograft function improved with high-doseIVIG therapy. The efficacy of high-dose IVIG in the eradica-tion of postrenal transplant B19 infection has been demon-strated previously (9,32). Positive seroconversion and long-term remission of recurrent anemia with IVIG therapy hasbeen reported in a renal transplant recipient despite per-sistence of viral genome (33). Nonetheless, in a series of13 renal transplant recipients with HLH, complete recov-ery was obtained in those received high-dose IVIG therapy(26).Finally, diagnosis of B19 infection requires a high indexof suspicion. Clinicians should consider this infection asa potential cause of HLH and TMA in renal transplantrecipients.References1. Fisman DN. Hemophagocytic syndromes and infection. Emerg In-fect Dis 2000; 6: 601–608.2. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R,Gould C. Infections associated with haemophagocytic syndrome.Lancet Infect Dis 2007; 7: 814–822.3. Koduri PR, Carandang G, DeMarais P, Patel AR. Hyperferritinemiain reactive hemophagocytic syndrome report of four adult cases.Am J Hematol 1995; 49: 247–249.4. Henter JI, Horne A, Aricó M et al. 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Postrenal transplant hemophagocytic lymphohistiocytosis and thrombotic microangiopathy associated with parvovirus B19 infection

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Postrenal transplant hemophagocytic lymphohistiocytosis and thrombotic microangiopathy associated with parvovirus B19 infection

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